AR082888A1 - PIRIDINE COMPOUNDS FOR THE INHIBITION OF NAMPT - Google Patents
PIRIDINE COMPOUNDS FOR THE INHIBITION OF NAMPTInfo
- Publication number
- AR082888A1 AR082888A1 ARP110103221A ARP110103221A AR082888A1 AR 082888 A1 AR082888 A1 AR 082888A1 AR P110103221 A ARP110103221 A AR P110103221A AR P110103221 A ARP110103221 A AR P110103221A AR 082888 A1 AR082888 A1 AR 082888A1
- Authority
- AR
- Argentina
- Prior art keywords
- aryl
- alkyl
- propenamide
- pyridinyl
- sulfonyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title abstract 4
- 102000015532 Nicotinamide phosphoribosyltransferase Human genes 0.000 title abstract 3
- 108010064862 Nicotinamide phosphoribosyltransferase Proteins 0.000 title abstract 3
- 230000005764 inhibitory process Effects 0.000 title 1
- 125000003118 aryl group Chemical group 0.000 abstract 13
- 125000000217 alkyl group Chemical group 0.000 abstract 10
- 125000001072 heteroaryl group Chemical group 0.000 abstract 6
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract 5
- 125000003545 alkoxy group Chemical group 0.000 abstract 4
- -1 cyano, amino Chemical group 0.000 abstract 3
- 125000001188 haloalkyl group Chemical group 0.000 abstract 3
- 125000005843 halogen group Chemical group 0.000 abstract 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 abstract 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract 2
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 2
- 229910052805 deuterium Inorganic materials 0.000 abstract 2
- 125000004438 haloalkoxy group Chemical group 0.000 abstract 2
- 229910052757 nitrogen Inorganic materials 0.000 abstract 2
- 125000004043 oxo group Chemical group O=* 0.000 abstract 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 2
- 125000001424 substituent group Chemical group 0.000 abstract 2
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 abstract 1
- FNCTVDSRLYABLX-UHFFFAOYSA-N 3-pyridin-3-yl-n-[3-[[3-(trifluoromethyl)phenyl]sulfamoyl]phenyl]prop-2-enamide Chemical compound FC(F)(F)C1=CC=CC(NS(=O)(=O)C=2C=C(NC(=O)C=CC=3C=NC=CC=3)C=CC=2)=C1 FNCTVDSRLYABLX-UHFFFAOYSA-N 0.000 abstract 1
- 229910003827 NRaRb Inorganic materials 0.000 abstract 1
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000005055 alkyl alkoxy group Chemical group 0.000 abstract 1
- 125000000304 alkynyl group Chemical group 0.000 abstract 1
- 125000004103 aminoalkyl group Chemical group 0.000 abstract 1
- 230000000259 anti-tumor effect Effects 0.000 abstract 1
- 239000000729 antidote Substances 0.000 abstract 1
- 229940075522 antidotes Drugs 0.000 abstract 1
- 125000005018 aryl alkenyl group Chemical group 0.000 abstract 1
- 125000004104 aryloxy group Chemical group 0.000 abstract 1
- 125000004429 atom Chemical group 0.000 abstract 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 125000004966 cyanoalkyl group Chemical group 0.000 abstract 1
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000005113 hydroxyalkoxy group Chemical group 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- AFOGFZPQMBSQBZ-UHFFFAOYSA-N n-(2-ethoxy-5-morpholin-4-ylsulfonylphenyl)-3-pyridin-3-ylprop-2-enamide Chemical compound CCOC1=CC=C(S(=O)(=O)N2CCOCC2)C=C1NC(=O)C=CC1=CC=CN=C1 AFOGFZPQMBSQBZ-UHFFFAOYSA-N 0.000 abstract 1
- OQYZHJDMXHBOPX-UHFFFAOYSA-N n-(3-cyclopentylsulfonylphenyl)-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NC(C=1)=CC=CC=1S(=O)(=O)C1CCCC1 OQYZHJDMXHBOPX-UHFFFAOYSA-N 0.000 abstract 1
- FUPSBQAMDUGOOF-UHFFFAOYSA-N n-(4-ethoxy-3-morpholin-4-ylsulfonylphenyl)-3-pyridin-3-ylprop-2-enamide Chemical compound C1=C(S(=O)(=O)N2CCOCC2)C(OCC)=CC=C1NC(=O)C=CC1=CC=CN=C1 FUPSBQAMDUGOOF-UHFFFAOYSA-N 0.000 abstract 1
- RXDVIZXSCOZBQI-UHFFFAOYSA-N n-(5-morpholin-4-ylsulfonyl-2-propan-2-yloxyphenyl)-3-pyridin-3-ylprop-2-enamide Chemical compound CC(C)OC1=CC=C(S(=O)(=O)N2CCOCC2)C=C1NC(=O)C=CC1=CC=CN=C1 RXDVIZXSCOZBQI-UHFFFAOYSA-N 0.000 abstract 1
- ZGYACXMMJDWEPK-UHFFFAOYSA-N n-[3-[(3-chlorophenyl)sulfamoyl]-4-methylphenyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C1=C(S(=O)(=O)NC=2C=C(Cl)C=CC=2)C(C)=CC=C1NC(=O)C=CC1=CC=CN=C1 ZGYACXMMJDWEPK-UHFFFAOYSA-N 0.000 abstract 1
- CEVCRNNROFJKCT-UHFFFAOYSA-N n-[3-[(4-chlorophenyl)sulfamoyl]-4-methylphenyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C1=C(S(=O)(=O)NC=2C=CC(Cl)=CC=2)C(C)=CC=C1NC(=O)C=CC1=CC=CN=C1 CEVCRNNROFJKCT-UHFFFAOYSA-N 0.000 abstract 1
- ZXWCHLTVHYOJHI-UHFFFAOYSA-N n-[5-(azepan-1-ylsulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl]-3-pyridin-3-ylprop-2-enamide Chemical compound FC(F)(F)COC1=CC=C(S(=O)(=O)N2CCCCCC2)C=C1NC(=O)C=CC1=CC=CN=C1 ZXWCHLTVHYOJHI-UHFFFAOYSA-N 0.000 abstract 1
- IMYLKEAIJMMKNL-UHFFFAOYSA-N n-[5-(diethylsulfamoyl)-2-morpholin-4-ylphenyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NC1=CC(S(=O)(=O)N(CC)CC)=CC=C1N1CCOCC1 IMYLKEAIJMMKNL-UHFFFAOYSA-N 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
La presente se relaciona con compuestos y composiciones para inhibir NAMPT (nicotinamida fosforribosiltransferasa), sus síntesis, aplicaciones y antídotos. Uso antitumoral.Reivindicación 1: Compuestos de fórmula (1) donde: Ar es arilo o heteroarilo, cada uno de dichos arilo y heteroarilo está sin sustituir u opcional e independientemente sustituido con 1, 2, 3 ó 4 sustituyentes los cuales pueden ser iguales o diferentes y se seleccionan independientemente del grupo que consiste en deuterio, halo, ciano, amino, aminoalquil-, (amino)alcoxi-, -CONH2, -C(O)NH(alquilo), -C(O)N(alquilo)2, -C(O)NH(arilo), -C(O)N(arilo)2, -CHzF3-z, -OCHzF3-z, -alquilo, -alquenilo, -alquinilo, -alcoxi, (alcoxialquil)amino-, -N(R3)-C(O)-alquilo, -N(R3)-C(O)-arilo, cicloalquilo, heterocicloalquilo, arilo y heteroarilo; R1 es -NRaRb, donde Ra es H, alquilo o -S(O)2alquilo y Rb es alquilo, hidroxialquilo, -S(O)2alquilo, -(CH2)q-cicloalquilo, -(CH2)q-heterocicloalquilo, arilo, arilalquil-, -(CH2)q-heteroarilo; cicloalquilo; heterocicloalquilo; arilo; heteroarilo; cada uno de dicho cicloalquilo, heterocicloalquilo, arilo, o heteroarilo está sin sustituir o sustituido con 1, 2, 3, 4 ó 5 sustituyentes los cuales pueden ser iguales o diferentes y se seleccionan independientemente del grupo que consiste en deuterio, halo, ciano, alquilo, hidroxilo, hidroxialquilo, hidroxialcoxi, cianoalquilo, haloalquilo, alquenilo, alquinilo, alcoxi, alquilalcoxi, haloalcoxi, arilalquenil-, ariloxi, benciloxi, oxo, -(CH2)q-NRcRd, -(CH2)q-CONRcRd, -S(O)2-alquilo, -S(O)2-arilo, -S(O)2NH2, -S(O)2NH-alquilo, -S(O)2N(alquilo)2, -S(O)2-heterocicloalquilo, -S(O)2-CF3, -C(O)alquilo, -C(O)arilo, -C(O)alquilenilarilo, -C(O)O-alquilo, -NH-C(O)alquilo, -NH-C(O)arilo, metilendioxi, -(CH2)q-cicloalquilo, cicloalquilalcoxi-, arilo, arilalquil-, -(CH2)q-heteroarilo, y -(CH2)q-heterocicloalquilo, donde cada uno de dicho cicloalquilo, heterocicloalquilo, arilo o heteroarilo puede ser sustituido por uno o más halo, nitro, haloalquilo, haloalcoxi, oxo, ciano, alquilo, haloalquilo, o alcoxi; y Rc y Rd se seleccionan independientemente del grupo que consiste en H, alquilo, hidroxialquilo, alcoxi, arilo, alcoxialquilo, -S(O)2alquilo y cicloalquilo o Rc y Rd pueden formar un grupo heterocicloalquilo de 5 ó 6 miembros junto con el átomo de nitrógeno al cual están unidos, donde dicho grupo heterocicloalquilo puede contener uno o más heteroátomos adicionales seleccionados entre N, S u O; z es 0, 1 ó 2; q es 0, 1, 2, 3 ó 4; y sus sales farmacéuticamente aceptables, con la condición de que el compuesto de fórmula (1) no sea N-[3-(ciclopentilsulfonil)fenil]-3-(3-piridinil)-2-propenamida; N-[4-etoxi-3-(4-morfolinilsulfonil)fenil]-3-(3-piridinil)-2-propenamida; N-[2-(1-metiletoxi)-5-(4-morfolinilsulfonil)fenil]-3-(3-piridinil)-2-propenamida; N-[2-etoxi-5-(4-morfolinilsulfonil)fenil]-3-(3-piridinil)-2-propenamida; N-[5-[(hexahidro-1Hazepin-1-il)sulfonil]-2-(2,2,2-trifluoretoxi)fenil]-3-(3-piridinil)-2-propenamida; N-[5-[(dietilamino)sulfonil]-2-(4-morfolinil)fenil]-3-(3-piridinil)-2-propenamida; N-[3-[[(3-clorofenil)amino]sulfonil]-4-metilfenil]-3-(3-piridinil)-2-propenamida; N-[3-[[(4-clorofenil)amino]sulfonil]-4-metilfenil]-3-(3-piridinil)-2-propenamida; 3-(3-piridinil)-N-[4-[[(tetrahidro-1,1-dioxido-3-tienil)amino]sulfonil]fenil]-2-propenamida; 3-(3-piridinil)-N-[3-[[[3-(trifluormetil)fenil]amino]sulfonil]fenil]-2-propenamida; y@@@3-(3-piridinil)-N-[1,4,5,6-tetrahidro-5-[(4-metilfenil)sulfonil]pirrolo[3,4-c]pirazol-3-il]-2-propenamida.This is related to compounds and compositions for inhibiting NAMPT (nicotinamide phosphoribosyltransferase), their synthesis, applications and antidotes. Antitumor use. Claim 1: Compounds of formula (1) wherein: Ar is aryl or heteroaryl, each of said aryl and heteroaryl is unsubstituted or optional and independently substituted with 1, 2, 3 or 4 substituents which may be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, amino, aminoalkyl-, (amino) alkoxy-, -CONH2, -C (O) NH (alkyl), -C (O) N (alkyl) 2 , -C (O) NH (aryl), -C (O) N (aryl) 2, -CHzF3-z, -OCHzF3-z, -alkyl, -alkenyl, -alkynyl, -alkoxy, (alkoxyalkyl) amino-, -N (R3) -C (O) -alkyl, -N (R3) -C (O) -aryl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R1 is -NRaRb, where Ra is H, alkyl or -S (O) 2alkyl and Rb is alkyl, hydroxyalkyl, -S (O) 2alkyl, - (CH2) q-cycloalkyl, - (CH2) q-heterocycloalkyl, aryl, arylalkyl-, - (CH2) q-heteroaryl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; each of said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents which may be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, alkyl, hydroxyl, hydroxyalkyl, hydroxyalkoxy, cyanoalkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylalkoxy, haloalkoxy, arylalkenyl-, aryloxy, benzyloxy, oxo, - (CH2) q-NRcRd, - (CH2) q-CONRcRd (CON O) 2-alkyl, -S (O) 2-aryl, -S (O) 2NH2, -S (O) 2NH-alkyl, -S (O) 2N (alkyl) 2, -S (O) 2-heterocycloalkyl , -S (O) 2-CF3, -C (O) alkyl, -C (O) aryl, -C (O) alkylenylaryl, -C (O) O-alkyl, -NH-C (O) alkyl, - NH-C (O) aryl, methylenedioxy, - (CH2) q-cycloalkyl, cycloalkylalkoxy-, aryl, arylalkyl-, - (CH2) q-heteroaryl, and - (CH2) q-heterocycloalkyl, where each of said cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be substituted by one or more halo, nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl, haloalkyl, or alkoxy; and Rc and Rd are independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxy, aryl, alkoxyalkyl, -S (O) 2alkyl and cycloalkyl or Rc and Rd can form a 5- or 6-membered heterocycloalkyl group together with the atom of nitrogen to which they are attached, wherein said heterocycloalkyl group may contain one or more additional heteroatoms selected from N, S or O; z is 0, 1 or 2; q is 0, 1, 2, 3 or 4; and its pharmaceutically acceptable salts, with the proviso that the compound of formula (1) is not N- [3- (cyclopentylsulfonyl) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [4-ethoxy-3- (4-morpholinyl sulfonyl) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [2- (1-Methylethoxy) -5- (4-morpholinyl sulfonyl) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [2-ethoxy-5- (4-morpholinyl sulfonyl) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [5 - [(hexahydro-1Hazepin-1-yl) sulfonyl] -2- (2,2,2-trifluorethoxy) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [5 - [(diethylamino) sulfonyl] -2- (4-morpholinyl) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [3 - [[(3-chlorophenyl) amino] sulfonyl] -4-methylphenyl] -3- (3-pyridinyl) -2-propenamide; N- [3 - [[(4-chlorophenyl) amino] sulfonyl] -4-methylphenyl] -3- (3-pyridinyl) -2-propenamide; 3- (3-pyridinyl) -N- [4 - [[(tetrahydro-1,1-dioxide-3-thienyl) amino] sulfonyl] phenyl] -2-propenamide; 3- (3-pyridinyl) -N- [3 - [[[3- (trifluoromethyl) phenyl] amino] sulfonyl] phenyl] -2-propenamide; and @@@ 3- (3-pyridinyl) -N- [1,4,5,6-tetrahydro-5 - [(4-methylphenyl) sulfonyl] pyrrolo [3,4-c] pyrazol-3-yl] - 2-propenamide
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| JP2010524844A (en) | 2007-04-26 | 2010-07-22 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Cinnamide compounds for dementia |
| WO2010066709A1 (en) | 2008-12-09 | 2010-06-17 | Topotarget A/S | Novel pyridinyl acrylamide derivatives |
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| FR2943675A1 (en) | 2009-03-24 | 2010-10-01 | Sanofi Aventis | ANTICANCER COMPOUNDS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| WO2010130178A1 (en) * | 2009-05-12 | 2010-11-18 | Sun Shuping | Acrylamide derivative and use thereof in manufacture of medicament |
| BR112013028281A2 (en) * | 2011-05-04 | 2017-01-10 | Forma Tm Llc | nampt inhibiting compounds and compositions |
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| WO2012150952A1 (en) | 2012-11-08 |
| CN103717574A (en) | 2014-04-09 |
| US20140275057A1 (en) | 2014-09-18 |
| RU2017112522A (en) | 2019-01-24 |
| RU2013153529A (en) | 2015-06-10 |
| KR20140027366A (en) | 2014-03-06 |
| US9169209B2 (en) | 2015-10-27 |
| TW201245152A (en) | 2012-11-16 |
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